1. Field of the Invention
Compositions for maintaining normal sexual function and treating sexual dysfunction in males and females comprising at least 15% by weight icariside I or at least 3.5% by weight anhydroicaritin, derived from extracts of plants belonging the Epimedium genus, are provided. Methods for maintaining normal sexual function and treating sexual dysfunction in both males and females are also provided, comprising oral administration of an effective amount of a novel composition of this invention comprising at least 15% by weight icariside I or at least 3.5% by weight anhydroicaritin.
2. Description of the Prior Art
The most prevalent type of sexual dysfunction in males is xe2x80x9cerectile dysfunctionxe2x80x9d, e.g., xe2x80x9cthe inability to achieve and/or maintain an erection sufficient for sexual activityxe2x80x9d (New England Journal of Medicine). Erectile dysfunction is most often attributable to the inability to generate enough NO in the corpus cavernosum.
The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP in turn stimulates protein phosphorylation by cGMP-dependent protein kinase G, thereby producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. The cGMP is eventually metabolized by the enzyme phosphodiesterase type V (PDE-5). This enzyme can be inhibited by certain drugs, resulting in an increased concentration of cGMP.
Various inhibitors of phosphodiesterases are known, including sildenafil citrate (Viagra(copyright)). Viagra(copyright) is an oral drug for erectile dysfunction made by Pfizer, Inc. Viagra(copyright) is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type V (PDE-5). Sildenafil enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type V (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE-5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.
Although Viagra(copyright) has the potential to help millions of men, and some women, it is not a sexual cure-all. It is not an aphrodisiac and therefore will not work in the absence of desire. Viagra also produces a number of unpleasant side effects. These include headaches (10% of test subjects), seeing the color blue (3% of test subjects, blackouts due to sudden drops in blood pressure, priapism or prolonged erections beyond 4 hours, and coital coronaries.
It would also be advantageous to provide a composition as described above which is effective for treating sexual conditions in females. It has been found that clitoral smooth muscle cells include many of the same morphological characteristics as the male corpus cavernosum, and should be physiologically responsive via the same messengers (cGMP) to promote smooth muscle relaxation (Park et al., Journal of Urology, v. 159, (Jun. 1998)). Thus, that which promotes smooth muscle relaxation in the corpus cavernosum, allowing inflow of blood, and alleviating erectile dysfunction, should work well to alleviate female sexual dysfunction. Indeed, women claim to experience benefit from Viagra(copyright) and clinical tests are now being performed.
Extracts of plants of the genus Epimedium have been used for centuries, particularly in traditional Chinese medicine, as aphrodisiacs and have been used to treat sexual dysfunction in males. Scientific studies have shown that when an extract of the leaves of Epimedium sagittatum is administered orally to laboratory animals, the frequency of copulation increases significantly. Another mode of action of Epimedium extracts is to dilate capillaries and other blood vessels, thereby facilitating circulation to the sexual organs as well as the brain.
A number of constituents contained in the aerial parts of Epimedium species have been isolated and characterized. The constituents of Epimedium have been reported as flavonoids, alkaloids, and lignans. Mizuno et al. (Phytochemistry (1987) 26:861-863; and Phytochemistry (1988) 27:3641-3643) have reported the presence of icariside I in extracts of Epimedium sagittatum. However, to the best of the inventors"" knowledge, there has been no study of the active components or metabolite(s) of Epimedium extracts which produce the desired effect of alleviating sexual dysfunction, nor have Epimedium extracts or any of the components of such extracts been evaluated for PDE-5 activity.
The present invention provides compositions enriched for icariside I and methods of obtaining such compositions from extracts of plants of the Epimedium genus. More specifically, the method of the present invention provides compositions comprising at least 15% by weight icariside I and methods for preparing the same.
A further object of this invention is to provide a method for producing compositions enriched for anhydroicaritin.
A further object of this invention is to provide compositions comprising at least 3.5% by weight anhydroicaritin.
A further object of the present invention is to provide a composition that is a PDE-5 inhibitor, wherein the composition comprises at least 15% by weight icariside I.
Another object of the present invention is to provide a composition that is a PDE-5 inhibitor, wherein the composition comprises at least 3.5% by weight anhydroicaritin.
Yet another object of this invention is to provide a method of inhibiting PDE-5 comprising administering to a subject an effective amount of a composition of this invention.
Further, the invention relates to methods and formulations for effectively treating sexual dysfunction or maintaining normal sexual function in males and females by orally administering a composition of this invention.
To achieve the foregoing and other objects and in accordance with the purposes of the present invention, as embodied and broadly described therein, one embodiment of this invention comprises a method of converting prenylated flavonol glycosides that are glycosylated at both the 3-position and the 7-position to a single compound, namely icariside I. More specifically, one embodiment of this invention comprises subjecting an Epimedium extract to mild acid hydrolysis to convert prenylated flavonol glycosides that are glycosylated at both the 3-position and the 7-position to one compound, namely icariside I. More specifically, one embodiment of this invention comprises a method of selectively hydrolyzing the 3-position glycoside units of compounds such as epimedium A, epimedium B, epimedium C, icariin, and their corresponding acetate derivatives without removing the 7-position glycoside of such compounds, to convert substantially all of such compounds present in the crude extract to icariside I. The resulting compositions obtained after mild acid hydrolysis according to the method of this invention comprise between about 15-60% by weight icariside I. The compositions obtained after acid hydrolysis are preferably purified to remove glycoside by-products and unreacted prenylated flavonol glycosides to yield compositions comprising between 15-60% by weight icariside I.
To further achieve the foregoing and other objects and in accordance with the purposes of the present invention, as embodied and broadly described therein, another embodiment of this invention comprises a method of producing a composition enriched in anhydroicaritin, the method comprising subjecting an Epimedium extract to mild acid hydrolysis to convert prenylated flavonol glycosides that are glycosylated at the 3-position and contain a hydroxyl group at the 7-position to one compound, namely anhydroicaritin. More specifically, one embodiment of this invention comprises a method of producing a composition enriched for anhydroicaritin, comprising subjecting an Epimedium extract to mild acid hydrolysis to hydrolyze the 3-position glycoside units of sagittatoside A, sagittatoside B, sagittatoside C, and the corresponding acetate derivatives to anhydroicaritin.
To further achieve the foregoing and other objects and in accordance with the purposes of the present invention, as embodied and broadly described therein, another embodiment of this invention comprises (1) subjecting an Epimedium extract to mild acid hydrolysis whereby the 3-position glycoside units of compounds such as epimedium A, epimedium B, epimedium C, icariin, and their corresponding acetate derivatives are selectively hydrolyzed to convert such compounds to icariside I, and the 3-position glycoside units of compounds such as sagittatoside A, sagittatoside B, sagittatoside C, and the corresponding acetate derivatives are hydrolyzed to convert such compounds to anhydroicaritin, thereby producing a composition enriched in icariside I and anhydroicaritin, and (2) subjecting this composition to enzymatic hydrolysis to hydrolyze the 7-position glycoside of icariside I to anhydroicaritin, thereby producing a composition further enriched in anhydroicaritin.
Other objects, features, and advantages of the present invention will become apparent from the following detailed descriptions. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.